Fingolimod-Associated Macular Edema

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Fingolimod is a disease-modifying therapy for relapsing-remitting multiple sclerosis (RRMS) that acts to modulate the sphingosine-1-phosphate receptor. Macular edema is a known dose-dependent side effect of fingolimod use that typically resolves upon discontinuation of the drug. It is important for the ophthalmologist to be aware of the pathophysiology, clinical manifestations, diagnostic methods, and management options in patients with fingolimod-associated macular edema (FAME).

Disease

Disease Entity

Fingolimod was the first FDA-approved oral disease-modifying therapy for the treatment of multiple sclerosis (MS). It acts by modulating the sphingosine-1-phosphate (S1P) receptor, preventing the release of lymphocytes into the systemic circulation and therefore reducing autoimmune demyelination in the central nervous system[1]. Macular edema (ME) has been reported as a significant ocular adverse event associated with the use of fingolimod for the treatment of MS and is termed fingolimod-associated macular edema (FAME).[2] Newer agents in the same class (e.g., Siponimod) have not been associated with the same risk of macular edema in clinical trials.

Pathophysiology

Macular edema (ME) is characterized by the accumulation of fluid in the outer plexiform layer and inner nuclear layer of the retina. This results from the breakdown of the blood-retinal barrier (BRB), causing the passage of proteins into the retinal tissues and osmotic water retention.[3] The BRB is maintained largely by tight junctions between vascular endothelial cells in the inner BRB and retinal pigmented epithelial cells (RPE) in the outer BRB (3). Breakdown of the BRB can be due to incompetence of the retinal vessels (e.g., diabetic ME), inflammation (e.g., uveitis, postsurgical), pathologic retinal membranes (e.g., tractional ME), compromised RPE cells (i.e., choroidal neovascularization) and medications (e.g., latanoprost, nicotinic acid, tamoxifen, thiazolidinediones).[4]

Fingolimod is a structural analog to S1P, a bioactive lipid that is involved in numerous immune and vascular processes.[4] The active metabolite of fingolimod, fingolimod-phosphate (fingolimod-P), binds to the S1P1 and S1P, receptors, and acts as a functional antagonist via internalization and degradation of these receptors.[5] Fingolimod’s therapeutic effect is mediated by binding of fingolimod-P to the S1P1 receptor, which leads to reversible retention of T cells in the lymph nodes, reducing the ability for these lymphocytes to contribute to central nervous system demyelination. While the exact mechanism of FAME is unknown, its development is likely also related to the antagonistic effect of fingolimod-P at these receptors. S1P1 antagonism by fingolimod may decrease pericytes and tight junctions between endothelial cells, increasing vascular permeability at the BRB, resulting in ME.[4][6][7]

Diagnosis

Symptoms

Patients with FAME may complain of decreased/blurred central vision, or change in color vision.[8] Patients may also report metamorphopsia, micropsia, or relative or absolute scotoma. Other patients may be asymptomatic.

Signs

Visual assessment may reveal decreased visual acuity, loss of contrast sensitivity (Pelli-Robson chart or similar), or dyschromatopsia. Metamorphopsia may be noted with Amsler grid assessment. Dilated fundus examination may reveal retinal thickening, intraretinal cysts, and alteration of the color of the macula. This may be seen better using green light.[8] Moderate to severe ME (foveal thickness >300 um) may be visible on slit lamp examination, while mild ME (foveal thickness of 201-300 um) is better detected through optical coherence tomography (OCT) imaging.[4] 

Imaging

OCT is a noninvasive modality that provides high resolution, cross-sectional images of the retina, and allows for a quantitative representation of retinal fluid distribution in ME. OCT allows for greater sensitivity in detecting changes in retinal thickness than slit lamp biomicroscopy, especially in mild ME. 

IVFA (intravenous fluorescein angiography) provides information on the quality of retinal perfusion through the visualization of retinal vessels. In ME, the early phase will reveal capillary dilation in the perifoveal region, and the late phase will show leakage of the fluorescein into the extravascular space, indicating increased vascular permeability. IVFA and OCT are highly sensitive for the detection of ME and is also useful in defining the etiology.[9]

Risk Factors

Patient age and coexisting conditions as well as the dose and duration of fingolimod treatment have been associated with a higher risk of developing FAME. In the FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral Therapy in MS) and TRANSFORMS (Trial Assessing Injectable Interferon vs FTY720 Oral in RRMS) trials, the risk of FAME was dose-dependent and occurred more often in patients on 1.25 mg vs. those taking 0.5 mg.[10][11] FAME occurred in 1% to 1.6% of patients on 1.25 mg compared to 0% to 0.5% in the 0.5 mg group. In a study of fingolimod with cyclosporine for renal transplant recipients, the risk of FAME was 2.2% and 1.3% in the groups receiving 5.0 mg and 2.5 mg, respectively.[12] The pooled data from the core and extension studies of these trials revealed that FAME occurred most often within 3-4 months of treatment onset but was also reported to develop over 12 months after starting fingolimod therapy.[13] Patient age >41 years and coexisting conditions like retinal vascular disease, diabetes mellitus, diabetic retinopathy, uveitis, and past ocular surgery also increased the risk of developing FAME.[13][14] 

Differential Diagnosis

Optic neuritis (ON) is an important diagnostic consideration in patients with MS who present with visual disturbance, but the clinical presentation is usually enough to distinguish the two. Important distinctions in presentation and ancillary studies are outlined in the table below.[4][15]

Symptom/Sign/Testing Macular Edema Optic Neuritis
Pain None Worse with eye movement
Visual Distortions Metamorphopsia Rarely metamorphopsia
RAPD None Common
OCT Macular thickening Early thickening and late thinning of the peripapillary

nerve fiber layer

IVFA Macular leakage Disc leakage
MRI Normal Optic nerve enhancement

RAPD = relative afferent pupillary defect; OCT = optical coherence tomography; IVFA = intravenous fluorescein angiography; MRI = magnetic resonance imaging

Management

General treatment

The management of FAME begins with stopping fingolimod treatment, which usually leads to resolution of the condition within 6 months.[10][11] Therefore, early detection is key and patients on fingolimod should have periodic ophthalmologic examinations with visual acuity, intraocular pressure, dilated fundus exam, slit lamp microscopy, and OCT. However, the decision to discontinue/change disease-modifying therapy must take into consideration the risk of worsening demyelinating disease.

Medical therapy

Apart from discontinuing fingolimod, there is no consensus about the proper management of FAME. Agents that have shown to improve the resolution of FAME include topical anti-inflammatory medications (e.g., nepafenac, bromfenac, ketorolac), corticosteroids (e.g., prednisolone, dexamethasone, difluprednate, triamcinolone), carbonic anhydrase inhibitors (acetazolamide) and anti-vascular endothelial growth factor (VEGF) antibodies (ranibizumab).[16][17][18][19][20][21][22] Most of these regimens involve discontinuing fingolimod, but some have been successful in the setting of continued fingolimod use.[19][21][23] However, there is a paucity of high-level evidence for any of these regimens due to the low incidence of FAME.[24]

Prognosis

The FDA recommends baseline ophthalmologic examination before initiating therapy with fingolimod and repeat studies at 3-4 months. This can be followed by re-examination 6 months later and then annually.[4] Patients with a history of uveitis, diabetes mellitus, or the use of other medications associated with ME should be monitored more closely. If FAME develops, resolution is achieved spontaneously in most patients after discontinuation of treatment, but refractory FAME may necessitate more intervention such as topical, subconjunctival, or intravitreal medications.

References

  1. Mandala S. Alteration of Lymphocyte Trafficking by Sphingosine-1-Phosphate Receptor Agonists. Science (80- ). 2002;296(5566):346-349. doi:10.1126/science.1070238
  2. Tedesco-Silva H, Pescovitz MD, Cibrik D, et al. Randomized Controlled Trial of FTY720 Versus MMF in De Novo Renal Transplantation. Transplantation. 2006;82(12):1689-1697. doi:10.1097/01.tp.0000251718.95622.b3
  3. Antcliff RJ, Marshall J. The Pathogenesis of Edema in Diabetic Maculopathy. Semin Ophthalmol. 1999;14(4):223-232. doi:10.3109/08820539909069541
  4. 4.0 4.1 4.2 4.3 4.4 4.5 Jain N, Bhatti MT. Fingolimod-associated macular edema: Incidence, detection, and management. Neurology. 2012;78(9):672-680. doi:10.1212/WNL.0b013e318248deea
  5. Subei AM, Cohen JA. Sphingosine 1-Phosphate Receptor Modulators in Multiple Sclerosis. CNS Drugs. 2015;29(7):565-575. doi:10.1007/s40263-015-0261-z
  6. ee M-J, Thangada S, Claffey KP, et al. Vascular Endothelial Cell Adherens Junction Assembly and Morphogenesis Induced by Sphingosine-1-Phosphate. Cell. 1999;99(3):301-312. doi:10.1016/S0092-8674(00)81661-X
  7. Lee J-F, Zeng Q, Ozaki H, et al. Dual Roles of Tight Junction-associated Protein, Zonula Occludens-1, in Sphingosine 1-Phosphate-mediated Endothelial Chemotaxis and Barrier Integrity. J Biol Chem. 2006;281(39):29190-29200. doi:10.1074/jbc.M604310200
  8. 8.0 8.1 Cugati S, Chen CS, Lake S, Lee AW. Fingolimod and macular edema: Pathophysiology, diagnosis, and management. Neurol Clin Pract. 2014;4(5):402-409. doi:10.1212/CPJ.0000000000000027
  9. Antcliff RJ, Stanford MR, Chauhan DS, et al. Comparison between optical coherence tomography and fundus fluorescein angiography for the detection of cystoid macular edema in patients with uveitis. Ophthalmology. 2000;107(3):593-599. doi:10.1016/S0161-6420(99)00087-1
  10. 10.0 10.1 Kappos L, Radue E-W, O’Connor P, et al. A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis. N Engl J Med. 2010;362(5):387-401. doi:10.1056/NEJMoa0909494
  11. 11.0 11.1 Cohen JA, Barkhof F, Comi G, et al. Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis. N Engl J Med. 2010;362(5):402-415. doi:10.1056/NEJMoa0907839
  12. Salvadori M, Budde K, Charpentier B, et al. FTY720 versus MMF with Cyclosporine in de novo Renal Transplantation: A 1-Year, Randomized Controlled Trial in Europe and Australasia. Am J Transplant. 2006;6(12):2912-2921. doi:10.1111/j.1600-6143.2006.01552.x
  13. 13.0 13.1 Zarbin MA, Jampol LM, Jager RD, et al. Ophthalmic Evaluations in Clinical Studies of Fingolimod (FTY720) in Multiple Sclerosis. Ophthalmology. 2013;120(7):1432-1439. doi:10.1016/j.ophtha.2012.12.040
  14. Hoitsma AJ, Woodle ES, Abramowicz D, Proot P, Vanrenterghem Y. FTY720 combined with tacrolimus in de novo renal transplantation: 1-year, multicenter, open-label randomized study. Nephrol Dial Transplant. 2011;26(11):3802-3805. doi:10.1093/ndt/gfr503
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  18. Chui J, Herkes GK, Chang A. Management of fingolimod-associated macular edema. JAMA Ophthalmol. 2013;131(5):694-696. doi:10.1001/jamaophthalmol.2013.47
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  20. Schröder K, Finis D, Harmel J, et al. Acetazolamide therapy in a case of fingolimod-associated macular edema: early benefits and long-term limitations. Mult Scler Relat Disord. 2015;4(5):406-408. doi:10.1016/j.msard.2015.06.015
  21. 21.0 21.1 Thoo S, Cugati S, Lee A, Chen C. Successful treatment of fingolimod-associated macular edema with intravitreal triamcinolone with continued fingolimod use. Mult Scler J. 2015;21(2):249-251. doi:10.1177/1352458514528759
  22. Pul R, Osmanovic A, Schmalstieg H, et al. Fingolimod associated bilateral cystoid macular edema—Wait and see? Int J Mol Sci. 2016;17(12). doi:10.3390/ijms17122106
  23. Akiyama H, Suzuki Y, Hara D, et al. Improvement of macular edema without discontinuation of fingolimod in a patient with multiple sclerosis A case report. Med (United States). 2016;95(29). doi:10.1097/MD.0000000000004180
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